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Build–couple–transform: a paradigm for lead-like library synthesis with scaffold diversity

DOI: 10.1021/acs.jmedchem.2c00897 DOI Help

Authors: Mélanie Uguen (Newcastle University) , Gemma Davison (Newcastle University) , Lukas J. Sprenger (Newcastle University) , James H. Hunter (Newcastle University) , Mathew P. Martin (Newcastle University) , Shannon Turberville (Newcastle University) , Jessica Watt (Newcastle University) , Bernard T. Golding (Newcastle University) , Martin E. N. Noble (Newcastle University) , Hannah L. Stewart (Newcastle University) , Michael J. Waring (Newcastle University)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Journal Of Medicinal Chemistry , VOL 65 , PAGES 11322 - 11339

State: Published (Approved)
Published: August 2022

Open Access Open Access

Abstract: High-throughput screening provides one of the most common ways of finding hit compounds. Lead-like libraries, in particular, provide hits with compatible functional groups and vectors for structural elaboration and physical properties suitable for optimization. Library synthesis approaches can lead to a lack of chemical diversity because they employ parallel derivatization of common building blocks using single reaction types. We address this problem through a “build–couple–transform” paradigm for the generation of lead-like libraries with scaffold diversity. Nineteen transformations of a 4-oxo-2-butenamide scaffold template were optimized, including 1,4-cyclizations, 3,4-cyclizations, reductions, and 1,4-additions. A pool-transformation approach efficiently explored the scope of these transformations for nine different building blocks and synthesized a >170-member library with enhanced chemical space coverage and favorable drug-like properties. Screening revealed hits against CDK2. This work establishes the build–couple–transform concept for the synthesis of lead-like libraries and provides a differentiated approach to libraries with significantly enhanced scaffold diversity.

Subject Areas: Biology and Bio-materials, Chemistry, Medicine

Instruments: I04-1-Macromolecular Crystallography (fixed wavelength)

Added On: 01/02/2023 08:38


Discipline Tags:

Health & Wellbeing Biochemistry Chemistry Structural biology Organic Chemistry Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)